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Update - Inpatient Diabetes and Hyperglycemia

Update - Inpatient Diabetes and Hyperglycemia. Review of Recent Developments in Context Greg Maynard MD, MSc UCSD. Outline. Background Infusion Insulin – Critical Care Transition from Infusion Clinical Inertia and SC insulin Hypoglycemia Transition Home – Glitazones

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Update - Inpatient Diabetes and Hyperglycemia

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  1. Update - Inpatient Diabetes and Hyperglycemia Review of Recent Developments in Context Greg Maynard MD, MSc UCSD

  2. Outline • Background • Infusion Insulin – Critical Care • Transition from Infusion • Clinical Inertia and SC insulin • Hypoglycemia • Transition Home – Glitazones • New Tools / Resources

  3. Inpatient Hyperglycemia and Poor Outcomes- Background • Robust physiologic rationale • Consistent dose-response relationship in dozens of observational / epidemiologic studies • Observations of non-RCT interventions (like Portland protocol, Krinsley) show benefit. • Influential RCTs showed benefit of tight glycemic control

  4. Intensive Insulin Therapy in Critically Ill Surgical Patients • Setting: Belgian SICU, University Hospital • Hypothesis: normalization of blood glucose levels with insulin therapy can improve prognosis of patients with hyperglycemia or insulin resistance • Design: prospective, RCT • Conventional: insulin when blood glucose > 215 mg/dL • Intensive: insulin when glucose > 110 mg/dL and maintained at 80–110 mg/dL van den Berghe G, et al. N Engl J Med.2001;345:1359–1367.

  5. Intensive Insulin Therapy in Critically Ill Patients * * * * * * * P < 0.01 Relative Risk reduction (%) Van-Den Berge et al, NEJM 345:1359, 2001

  6. AACE - Consensus Conference Blood Glucose Targets • Upper Limit Inpatient Glycemic Targets: • ICU: 110 mg/dl (6.1 mmol/L) • Non-critical care (limited data) • Pre-prandial: 110 mg/dl (6.1 mM) • Maximum: 180 mg/dL (10 mM) The current ADA guideline for pre-prandial plasma glucose levels is 90–130 mg/dl AACE- Endocrine Practice 10 (1): 77-82, 2004 ADA- Diabetes Care 27: 553-591, 2004

  7. Things Get More Complicated

  8. Intensive Insulin Therapy in the Medical ICU Greet Van den Berghe, M.D., Ph.D., and the Leuven Group N Engl J Med, Volume 354;5:449-461, February 2, 2006 • RCT of insulin infusion to goal of 80-110 mg/dL vs usual therapy (180-200 mg/dL). • 1,200 patients randomized • A priori outcome of interest: patients in MICU for > 3 days • Only 17% were diabetic

  9. ICU LOS > 3 Days p: 0.009 p: 0.05 52.5 43.0 % % 38.1 31.3 ICU mortality Hospital mortality Mortality Reduction 17.9% Mortality Reduction 18.1% Intensive Insulin Therapy in MICU: Hospital Mortality Conventional treatment Intensive treatment Intention to Treat p: 0.33 p: 0.31 40 37.3 26.8 24.2 ICU mortality Hospital mortality Hazard ratio 0.94 (95 CI 0.84 – 1.06) Van-Den Berge et al, NEJM 354:449-61, 2006

  10. Conclusions: MICU study • Intensive insulin therapy significantly reduced overall morbidity but not mortality. • Predefined population analysis (ICU > 3 d): • In-house mortality reduced (ARR 9.5%) • ICU mortality reduced (ARR 7.2%) p=.05 • Morbidity Reduced • BUT, More deaths (18.8 vs 26.8%) in patients in ICU < 3 days (NS w/ adjustment) • More studies needed.

  11. Efforts to Validate The Goals Coming from the Van den Berghe Trials • Glucontrol • VISEP • NICE-SUGAR

  12. Glucontrol Study (abstract info) • Mixed population of ICU patients • N = ~3500, multicenter, Europe • Target glucose: • 80 – 110 mg/dl vs. 140 – 180 mg/dl • Endpoint: in-hospital and 28 day mortality • Start: October 2004

  13. GLUCONTROL Group A (n = 550) Group B (n = 551) P Age, yr 65 (51-74) 65 (51 – 74) 0.9207 Sex ratio, M/F 352/198 338/213 0.3827 Category Medical Scheduled Surgery Emergency Surgery Trauma 42.9 % 31.3 % 18.1 % 7.7 % 41.2 % 32.7 % 18.1 % 7.9 % 0.9437 Philippe Devos, MD Jean-Charles Preiser MD, PhD University Hospital of Liège - Belgium

  14. GLUCONTROL 300 p < 0.0001 250 200 Blood glucose, mg/dl 147 mg/dl 150 119 mg/dl 100 50 Group A Group B

  15. GLUCONTROL Hypoglycemia 8.6% vs 4% Median (IQR)

  16. VISEP Trial Brunkhorst et al, N Engl J Med 358:125-39, 2008

  17. VISEP Trial Study Aim: to evaluate clinical outcome in 600 subjects with sepsis randomized to conventional or intensive insulin therapy in 18 academic hospitals in Germany. Conventional Therapy: CII started at BG > 200 mg/dl and adjusted to maintain a BG 180 - 200 mg/dl. Intensive Therapy group: CII started at BG > 110 mg/dl and adjusted to maintain BG 80 -110 mg/dl (Leuven’s protocol) Primary Outcomes: Mortality (28 days) and morbidity (sequential organ failure dysfunction, SOFA) Safety end-point: hypoglycemia (BG<40 mg/dl) Brunkhorst et al, N Engl J Med 358:125-39, 2008

  18. IIT (n = 247) CIT (n = 290) P Mortality rate, % - 28 days - 90 days 24.7% 39.7% 26% 35.4% 0.74 0.31 < 0.0001 Patients with hypoglycemia < 40, % 17.0 % 4.1 % SOFA Score 7.7 7.3-8.3 7.8 7.3-8.3 0.16 VISEP Trial- Data from 488 patients: IIT [goal: 80 – 110 mg/dL]: mean BG 112 mg/dl CIT [goal: 180 – 200 mg/dL]: mean BG 151 mg/dl Brunkhorst et al, N Engl J Med 358:125-39, 2008

  19. Delta GlucoseIntervention vs Control Leuven I 50 mg / dL VISEP 39 mg / dL Glucontrol 28 mg / dL

  20. Severe Hypoglycemia (< 40 mg / dL) with Different Infusion Protocols Leuven I - (Surgical) 5.1% Leuven 2 (Medical) 19% Glucontrol (Med / Surg) 8.6% VISEP (Medical) 17% Yale (Surgical) 0% Yale (Medical) 4.3% Glucommander (Surgical) 2.6% Van Den Berghe G, et al. N Engl J Med. 2001:345:1359; Van Den Berghe G, et al. N Engl J Med. 2006;354:449-461; Brunkhorst et al, N Engl J Med 358:125-39, 2008 Goldberg PA, et al. Diabetes Care. 2004;27:461; Goldberg PA, et al. J Cardiothorac Vasc Anes. 2004;18:690; Davidson PC. Diabetes Care. 2005;28:2418.

  21. Infusion Protocols – Variable Hypoglycemia Rates

  22. Comparison of Insulin Infusion Protocols in the ICU: Computer-Guided Versus Standard Column-Based Insulin Regimens CHRISTOPHER A. NEWTON, DAWN SMILEY, PAUL DAVIDSON, BRUCE BODE, DENNIS STEED, SOL JACOBS, ABBAS E. KITABCHI, FRANKIE STENTZ, ANGEL TEMPONI, PATRICK MULLIGAN,GUILLERMOE. UMPIERREZ, Atlanta, GA, Memphis, TN 2008 ADA Abstract

  23. Summary Recent Insulin Infusion Studies • Recent negative studies • Glucontrol, VISEP • Caveats • Used Leuven protocol (viewed as suboptimal) • Delta Glucose less than desirable • Very high hypoglycemia rates seen in these studies….3 x hypoglycemia rate seen in U.S. • NICE – SUGAR out soon

  24. Infusion Insulin Take Home Points • Surgical Populations easier • Protocols vary greatly • Automated protocols promising • Need to monitor control and hypoglycemia • < 5% of patients w/ glucose < 40 mg / dL is a reasonable goal • Optimal glycemic target debatable • Different targets for different groups? • Where are you at?

  25. “The days if ignoring blood sugar levels or tolerating marked hyperglycemia in the ICU (which was common place) are over.” Malhotra, NEJM 354:516, 2006

  26. Transitions

  27. Transition from Infusion InsulinRamos, Childers, Maynard – SHM Abstract N = 41

  28. Nurse Mandated Transition from IV insulin to SC Basal Bolus Insulin Criteria for Transition: • History of diabetes • HbA1c >6% Methodology: • Glargine SC given at HS POD #1 if able to eat • IV insulin discontinued at noon POD#2 post am meal insulin Davidson, Bode et al, May 2008 JDST pub pending

  29. Transition to SubQ Managed by Anesthesiology in Operating Room SubQ Basal-Bolus Glucommander 0 12 24 36 48 60 hours

  30. Transition from Glucommander to Basal-Bolus Insulin Glargine and Aspart Basal: Multiplier * 500; CIR: 0.5 / Multiplier; Correction Factor: 1.7 / Multiplier n=209 Blood Glucose (mg/dl) Hours after IV insulin Breakfast Breakfast Breakfast Bedtime Bedtime Bedtime Last GM 3:00AM 3:00AM Dinner Lunch 3:00AM Dinner Dinner Lunch Lunch Davidson, Bode et al, May 2008 JDST pub pending

  31. Transition from infusion insulinTake Home Points • Transition is opportunity for failure • Protocols can / should address this • Insulin multiplier method safe / effective • Comparisons of transition methods needed • Patients with stress hyperglycemia do OK without transition to basal - bolus regimen

  32. More Evidence for Clinical Inertia • Retrospective Analysis • Teaching hospital (200 bed; metro. Phoenix) • LOS 3 or more days; non-ICU • 2,916 / 7,361 discharges with DM or HG diagnosis • Average age 69 yrs; 90% white • ALOS 5.7 days Cook CB, et al JHM2007; 2:203-211

  33. Not much movement…. First 24 hrs Stay Last 24 hrs Cook CB, et al. J Hosp Med 2007; 2: 203-211

  34. Insulin dosing Δ insulin dose from first to last 24hr period • 54% (n=1680) increased (avg 17 units) • 39% decreased (avg 12 units) • 7% no change Heterogeneous patterns of change within tertiles Increase in dose with rising hyperglycemia 1st tertile 41% on more insulin by d/c 3rd tertile 65% on more insulin; 31% less by d/c Cook CB, et al. J Hosp Med 2007; 2: 203-211

  35. Conclusions • Glycemic control poor • Suboptimal use of insulin even when sustained hyperglycemia present (clinical inertia) • Education should focus on importance of inpatient BG control and provide guidelines on how and when to change hyperglycemia therapy Cook CB, et al. J Hosp Med 2007; 2: 203-211

  36. RCTs with demonstrating convincing benefit of TGC on general med – surg wards:

  37. Randomized Basal Bolus versus Sliding Scale Regular Insulin Therapy in patients with type 2 Diabetes (RABBIT-2 Trial) Study Type: Prospective, randomized, open-label trial Patient Population: 130 subjects with DM2 Oral hypoglycemic agents or insulin therapy Study Sites: Grady Memorial Hospital, Atlanta Jackson Memorial Hospital, Miami

  38. (RABBIT-2 Trial) Basal / Bolus arm • D/C oral antidiabetic drugs on admission • Starting total daily dose (TDD): • 0.4 U/kg/d x BG between 140-200 mg/dL • 0.5 U/kg/d x BG between 201-400 mg/dL • Half of TDD as insulin glargine and half as rapid-acting insulin (lispro, aspart, glulisine) • Insulin glargine - once daily, at the same time/day. • Rapid-acting insulin- three equally divided doses (AC) Smiley & Umpierrez, Southern Med J, June 2006

  39. Mean Blood Glucose Levels During Insulin Therapy * * * ¶ ¶ ¶ ¶ * p<0.01 ¶ p<0.05 Day 3: P=0.06 Umpierrez, Diabetes Care 30: 2007

  40. Blood Glucose Levels in Patients Who Failed SSRI: Transition to Basal Bolus Insulin P: 0.02 P: NS ¶ ¶ ¶ ¶ ¶ Failure was defined as 3 consecutive BG values > 240 mg/dL during SSRI Umpierrez, Diabetes Care 30: 2007

  41. RABBIT 2 • Improved glycemic control with basal / bolus insulin regimen compared to SSRI • Subset that failed with SSRI controlled with basal / bolus • No difference in hypoglycemia Umpierrez, Diabetes Care 30: 2007

  42. Improving Glycemic Control in Medical Inpatients: A Pilot Study • Implement SC Insulin Protocol on Med Service n = 89 • Monitor acceptance and effect on hypoglycemia, insulin use, glycemic control • Compare to prior observational study n = 91 Trujillo et al with JL Schnipper JHM 3:1 55-64

  43. Results • Resident acceptance poor - 56% • Reluctant to start and adjust Baseline Protocol p Basal insulin 49% 64% 0.05 Nutritional insulin 0% 13% <0.001 Any hypoglycemia 7% 13% 0.20 ns Glycemic control not significantly improved If you build it, will they come?

  44. Effect of Structured Insulin Orders and an Insulin Management Algorithm • 400 bed academic center • All adult monitored stays on Med / Surg wards with dx of DM or Documented Hyperglycemia n = 9,314 > 7 readings n = 5,530 • What is effect of implementing a structured insulin order set? • What is the incremental effect of an insulin management protocol? • Outcomes • Insulin Use Patterns • Glycemic Control • Hypoglycemia Maynard et al, JHM publication pending 2008

  45. The Use of Basal Insulin Increases(sliding scale only regimens decline) 72% of 477 insulin regimens SSI only in May-Oct 2003 vs 26% of 499 in Mar-Aug 2004

  46. % of 9,314 Patient-Stays with Uncontrolled Hyperglycemia

  47. A Win / Win Situation5,530 patients with DM or Hyperglycemia and > 7 POC Glucose readings TP3:TP1 RR Uncontrolled Patient-Day 0.77 (0.74 - 0.80) RR Uncontrolled Patient-Stay 0.73 (0.66 - 0.81) RR Hypoglycemic Patient-Day 0.68 (0.59 – 0.80) RR Hypoglycemic Patient-Stay 0.77 (0.64 – 0.92) Maynard et al, JHM publication pending 2008

  48. Hypoglycemia

  49. Hypoglycemia in Hospitalized Patients Treated with Antihyperglycemic Agents • Setting: 675 bed university hospital • 2,174 monitored patients received glucose lowering agents in 3 months • 206 (9.5%) had one or more BG < 60 within 48 hrs of Rx with antihyperglycemic agent • 484 hypoglycemic events (44% more than one event) 29% in DM 1 23% in ICU 72% in those Rxd with insulin alone Varghese P, et al. J Hosp Med. 2007; 2:234-240)

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